1. Field of Invention
The present invention relates to novel compounds and processes. In particular, the invention relates to novel analogs of the aminocyclitol antibiotic spectinomycin. More particularly, it relates to novel processes for synthesizing analogs of spectinomycin; both known analogs and the novel analogs of the present invention. Additionally, the invention includes novel intermediates.
The novel analogs of spectinomycin disclosed herein are useful as antimicrobial agents.
Spectinomycin is the compound illustrated, with numbering of carbon positions in formula I.sub.1.
The present invention relates to novel C-6' analogs, including novel analogs of the 5'-desmethyl analog, of spectinomycin illustrated in formula I' wherein E'.sub.1 and E'.sub.2 may be the same or different, and are as follows:
(a) E'.sub.1 is hydrogen and E'.sub.2 is aryl or an essentially hydrocarbyl substituent with the proviso that the hydrocarbyl may not be aminoalkyl, hydroxy alkyl, alkoxy alkyl, and that when the substituent is haloalkyl then at least one halo atom is on a carbon of the alkyl other than the terminal carbon.
(b) E'.sub.1 and E'.sub.2 are the same or different and are selected from the group consisting of hydrogen and C(O)OR'.sub.2 wherein R'.sub.2 is hydrogen, alkyl of from 1 to 8 carbon atoms, inclusive, or aryl, with the proviso that E'.sub.1 and E'.sub.2 cannot both be hydrogen or
(c) E'.sub.1 and E'.sub.2 are the same or different and are hydrogen or CN with the proviso that E'.sub.1 and E'.sub.2 cannot both be hydrogen.
The present invention also relates to novel analogs of C-6' analogs (formula I') in which the hydrogen atoms attached to each of the nitrogen atoms bonded to C-1 and C-3 (analogous to the numbering of carbon positions illustrated in formula I.sub.1) in the molecules are replaced by a blocking group, i.e., B is hydrogen or a blocking group.
Unless otherwise qualified, reference herein to C-6' analogs of spectinomycin, includes both references to the aforementioned novel C-6' analogs and known C-6' analogs of spectinomycin shown by the formula I which C-6' analogs further includes analogs with the nitrogen atoms bonded to C-1 and C-3 blocked, i.e., B is hydrogen or a blocking group.
Blocking groups referred to above are sometimes called "protective groups" in the art and are well known in many fields of organic chemistry, including peptide chemistry, fatty acid chemistry and especially semi-synthetic and synthetic antibiotic chemistry. Two commonly used blocking groups are carbobenzyloxy and t-butoxycarbonyl. Such groups can be removed easily and replaced by hydrogen atoms with suitable treatments, which may vary in detail depending on the particular blocking group and the particular molecule to which it is bonded, with acids or by reduction. A quite comprehensive list of blocking groups which can be attached to spectinomycin analogs is disclosed in U.S. Pat. No. 4,173,647, the selection, preparation, use and removal of which is incorporated herein by reference. Regarding the chemistry of adding and removing such blocking, see. e.g., Boissona, Adv. Org. Chem. 3, 159 (1963) and Windholz et al., Tetrahedron Lett. 8, 2555 (1967).
Spectinomycin itself is a known natural product. See Bergy et al., U.S. Pat. No. 3,234,092. Numerous spectinomycin analogs in which the nitrogen atom bonded to C-1 and C-3 are blocked are also known. See White, inventor of both, U.S. Pat. Nos. 4,351,771 and 4,361,701; Federal Republic of Germany Offenlegungschriften Nos. 2,756,912 (Derwent Farmdoc Accession No. 50959B) and 2,756,913 (Derwent Farmdoc Accession No. 40960B). The White patents include numerous C-6' analogs including the 5'-desmethyl analog, of spectinomycin as well as such analogs with nitrogen atoms bonded to C-1 and C-3 blocked.
The present invention also concerns novel synthetic processes. In particular, it concerns;
(i) the novel synthesis of C-6' analogs of spectinomycin of formula I wherein E.sub.1 and E.sub.2 may be the same or different and are PA0 (ii) the novel synthesis of a novel intermediate illustrated by the formula II wherein E.sub.1 and E.sub.2 are as defined above; B.sub.1 is a blocking group from among those blocking the nitrogen atoms bonded to C-1 and C-3 as discussed above; and B.sub.2, B.sub.3 and B.sub.4 are oxygen protecting groups; PA0 (iii) the novel synthesis of a novel intermediate illustrated by the formula III wherein E.sub.1 and E.sub.2 are as defined above; B.sub.1, B.sub.2, B.sub.3 and B.sub.4 are as defined above; PA0 (iv) the novel synthesis of a novel intermediate illustrated by the formula IV wherein B.sub.1, B.sub.2, B.sub.3 and B.sub.4 are as defined above; PA0 (v) the novel synthesis of a novel intermediate illustrated by the formula V wherein B.sub.1, B.sub.2 and B.sub.3 are as defined above; PA0 (vi) the novel synthesis of a novel N-protected actinamine having selected oxygen atom protection illustrated by the formula VI wherein B.sub.1 and B.sub.2 are as defined above. PA0 McOmie, J. F. Protective Groups in Organic Chemistry, Plenum Press (1973), PA0 Green, T. W. Protective Groups in Organic Synthesis, Wiley (1981). PA0 (A) A compound of formula I' PA0 wherein B is PA0 (B) A process for preparing a compound of formula I, PA0 wherein E.sub.1 and E.sub.2 may be the same or different and are PA0 wherein B is PA0 which comprises PA0 wherein E.sub.1 and E.sub.2 are as defined above, and PA0 wherein B.sub.1 is a blocking group, and PA0 wherein B.sub.2, B.sub.3 and B.sub.4 are oxygen protecting groups; with an oxygen deblocking agent, for example, hydrogen fluoride when the blocking group contains silicon and recovering a compound having the formula I PA0 wherein B is a blocking group, or PA0 wherein E.sub.1 and E.sub.2, B.sub.1, B.sub.2, B.sub.3 and B.sub.4 are as defined above; with an oxygen deblocking agent, for example, hydrogen fluoride when the blocking group contains silicon and recovering a compound of formula I PA0 wherein B is a blocking group; and replacing the blocking group with hydrogen to obtain a compound of formula I PA0 wherein B is hydrogen. PA0 (C) A process for preparing a compound of formula II wherein E.sub.1, E.sub.2, B.sub.1, B.sub.2, B.sub.3 and B.sub.4 are as defined above which comprises treating a compound having the formula III wherein E.sub.1, E.sub.2, B.sub.1, B.sub.2, B.sub.3 and B.sub.4 are as defined above; with step (a) Na.sub.2 CO.sub.3 and then step (b) m-chloroperbenzoic acid to obtain the compound of formula II. PA0 (D) A process for preparing a compound of formula III PA0 (E) A process for preparing a compound of formula IV PA0 (F) A process for the preparation of a compound of formula V PA0 (G) A process for the preparation of a compound of formula VI. PA0 (H) A compound having the formula II PA0 (I) A compound having the formula III PA0 (J) A compound having the formula IV PA0 (K) A compound having the formula V PA0 (L) A compound having the formula VI
(a) hydrogen, PA1 (b) alkyl of from 1 to 8 carbon atoms, inclusive, with the proviso that only E.sub.2 is alkyl, PA1 (c) essentially hydrocarbyl, with the proviso that only E.sub.2 is hydrocarbyl, PA1 (d) aryl, with the proviso that only E.sub.2 is aryl, PA1 (e) C(O)OR.sub.2 wherein R.sub.2 is hydrogen, alkyl of from 1 to 8 carbon atoms, inclusive, or aryl or PA1 (f) CN; PA1 (a) E'.sub.1 is hydrogen and E'.sub.2 is aryl or an essentially hydrocarbyl substituent with the proviso that the hydrocarbyl may not be aminoalkyl, hydroxy alkyl, alkoxy alkyl, and that when the substituent is haloalkyl then at least one halo atom is on a carbon of the alkyl other than the terminal carbon. PA1 (b) E'.sub.1 and E'.sub.2 are the same or different and are selected from the group consisting of hydrogen and C(O)OR'.sub.2 wherein R'.sub.2 is hydrogen, alkyl of from 1 to 8 carbon atoms, inclusive, or aryl, with the proviso that E'.sub.1 and E'.sub.2 cannot both be hydrogen or PA1 (c) E'.sub.1 and E'.sub.2 are the same or different and are hydrogen or CN with the proviso that E'.sub.1 and E'.sub.2 cannot both be hydrogen. PA1 (a) hydrogen or PA1 (b) a blocking group. PA1 (a) hydrogen, PA1 (b) alkyl of from 1 to 8 carbon atoms, inclusive, with the proviso that only E.sub.2 is alkyl, PA1 (c) essentially hydrocarbyl, with the proviso that only E.sub.2 is hydrocarbyl, PA1 (d) aryl, with the proviso that only E.sub.2 is aryl, PA1 (e) C(O)OR.sub.2 wherein R.sub.2 is hydrogen, alkyl of from 1 to 8 carbon atoms, inclusive, or aryl or PA1 (f) CN; PA1 (a) hydrogen or PA1 (b) a blocking group PA1 (a) treating a compound of formula II PA1 (b) treating a compound of formula II PA1 wherein E.sub.1, E.sub.2, B.sub.1, B.sub.2, B.sub.3 and B.sub.4 are as defined above; PA1 which comprises treating a compound having the formula IV PA1 wherein B.sub.1, B.sub.2, B.sub.3 and B.sub.4 are as defined above; with a compound having the formula VII PA1 wherein E.sub.1 and E.sub.2 are as defined above; in the presence of an Lewis acid catalyst such as tris(6,6,7,7,8,8,8-heptafluoro)-2,2-di-methyl-3,5-octanedionate to obtain the compound of formula III PA1 wherein B.sub.1, B.sub.2, B.sub.3 and B.sub.4 are as defined above PA1 which comprises treating a compound of formula V PA1 wherein B.sub.1, B.sub.2, B.sub.3 and B.sub.4 are as defined above; with an oxygen protecting group, such as t-butyldimethylsilyl triflate, in the presence of an amine base, such as triethylamine. PA1 wherein B.sub.1, B.sub.2, B.sub.3 and B.sub.4 are as defined above; PA1 which comprises treating a compound having the formula VI PA1 wherein B.sub.1 and B.sub.2 are as defined above; with 3-(acetyloxy)-4-methoxy-3-buten-2-one in the presence of p-toluenesulfonic acid and heated to the distillation temperature of essentially pure solvent, such as benzene to obtain the compound V. PA1 wherein B.sub.1 and B.sub.2 are as defined above; PA1 which comprises PA1 (a) treating a compound having the formula I.sub.1 wherein the nitrogen atoms bonded to C-1 and C-3 are protected; in a solvent, such as methanol, with sodium methoxide and then neutralizing the solution with acetic acid to obtain a compound having the formula VIII wherein B.sub.1 is as defined above; PA1 (b) treating the compound of (a) in a solvent, such as dimethylformide with an oxygen protecting group in the presence of imidazole to obtain a compound having the formula IX PA1 wherein B.sub.1 and B.sub.2 are as defined above and PA1 (c) treating the compound of (b) in a solvent, such as methanol with acetylchloride to obtain the compound VI. PA1 wherein E.sub.1, E.sub.2, B.sub.1, B.sub.2, B.sub.3 and B.sub.4 are as defined above. PA1 wherein E.sub.1, E.sub.2, B.sub.1, B.sub.2, B.sub.3 and B.sub.4 are as defined above. PA1 wherein B.sub.1, B.sub.2 and B.sub.3 are as defined above. PA1 wherein B.sub.1, B.sub.2 and B.sub.3 are as defined above. PA1 wherein B.sub.1 and B.sub.2 are as defined above.
Finally, the present invention also relates to the above noted novel intermediates II, III, IV, V and VI.
Oxygen protecting groups as referred to above are selected from a variety known in the practice of synthetic organic chemistry, including reactions of various dienes with suitable dienophiles, for example, as reviewed by Danishefsky, "Siloxy Dienes in Total Synthesis", Accounts of Chemical Research, vol. 14, pp. 400-6 (1981). Other examples of appropriate oxygen protecting groups for use in the present invention can be found in references as follows:
Oxygen protecting groups which can be attached as B.sub.2, B.sub.3 and B.sub.4 in the novel intermediates of the above processes are t-butyldiphenylsilyl, t-butyldimethylsilyl, acetyl or propionyl and the like. t-Butyldiphenylsilyl is preferred as B.sub.2, t-butyldimethylsilyl is preferred as B.sub.4, and an acetyl group is preferred as B.sub.3.
All of the intermediates of the present invention which contain one or more oxygen blocking groups are useful intermediates in processes for making successive intermediates in processes for making C-6' analogs of spectinomycin of the present invention process which contain blocking groups on the nitrogen atoms bonded to C-1 and C-3. Replacement of the blocking groups by hydrogen on the nitrogen atoms bonded to C-1 and C-3 in C-6' analogs of spectinomycin of the present invention process provides C-6' analogs of spectinomycin having the formula I which are useful as antimicrobial agents.
The present invention also includes the pharmacologically acceptable acid addition salts of the novel antimicrobial C-6' analogs of spectinomycin having the formula I' disclosed herein.
2. Prior Art
There are few references to spectinomycin analogs with modified sugar rings in the literature, and none of these involve compounds having E'.sub.1 and E'.sub.2 as defined for the novel analogs of the present invention. For example, see U.S. Pat. Nos. 4,351,771; 4,361,701 and 4,173,647.
Modification at the C-6' position to produce spectinomycin analogs with modified sugar rings is known. However, previously known modification does not use the novel processes or intermediates and does not disclose the novel analogs of the present invention. Such previously known modification at the C-6' position can be found in U.S. Pat. Nos. 4,351,771 and 4,361,701 as well as in U.S. application Ser. No. 449,304, filed Dec. 13, 1982, now U.S. Pat. No. 4,532,336 which is a continuation-in-part of U.S. application Ser. No. 359,723, filed March, 1982, now abandoned. The latter noted continuation-in-part application describes the now more preferred modifications at the C-6' position and is, therefore, incorporated herein by reference. Again, none of the prior disclosures of the above cited references make obvious the present invention. Particularly, these references provide no enablement for the wide variety of substituents of the present invention at the C-6' position.
An early discussion of spectinomycin chemistry by Wiley et al., "The Chemistry of Actinospectacin. IV. The Determination of the Structure of Actinospectacin", J. Am. Chem. Soc., vol. 85, pp. 2652-9, Sept. 5, 1963, includes a compound useful in the determination of the structure of spectinomycin similar to a precursor now found useful in the process to make the novel protected actinamine having the formula VI of the present invention. However, Wiley et al. make no suggestion that such a novel actinamine of formula VI is obvious or can be made and further provides no teaching which would make it obvious to try to make the novel actinamine of the present invention.
On the other hand, White et al., in "Synthesis and In Vitro Antibacterial Properties of Alkylspectinomycin Analogs", The Journal of Antibiotics, vol. XXXVI, No. 3, pp. 339-42, Mar., 1983, discuss, as presently understood, preferred alkylspectinomycin analogs which can now be made by the present invention process.
The Diels-Alder reaction is one well known in synthetic chemistry. See the textbook, March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, McGraw-Hill Book Company, pp. 626-636, 1968, or more recently for the Diels-Alder reactions using siloxy dienes, see Danishefsky, "Siloxy Dienes in Total Synthesis", Accounts of Chemical Research, vol. 14, pp. 406-6, 1981. Finally, more specifically, David et al. "Stereochimie de la Cycloaddition sur les Ethers Butactienyliques d'Alcook Chiraux. Derives en 4 et 6 de Glucosides Perbenzyles", Tetrahedron, vol. 34, pp. 299-304, 1978, discuss preparation of derivatives of perbenzyl glucosides from partially protected derivatives of .alpha.-D-glucose in a reaction of cycloaddition onto butadienyl ethers of chiral alcohols. However, the above disclosures in no way make obvious or suggest the use of a Diels-Alder type reaction to obtain the spectinomycin analogs having C-6' modification of the present invention.